The open-end battle of mankind against disease-causing microorganisms dates back to an era many years before Robert Koch and Louis Pasture's discoveries relating microorganisms as causative agents of disease. Since the early 1900's this era has been followed by the heroic efforts of microbiologists, biochemists and chemist to pave the road by their rigorous research studies to identify natural as well as synthetic sources of antimicrobial agents, including those derived from plants, marine organisms and microorganisms. In this regard, the first report on synthetic antimicrobials, sulfonamides, dates back to the mid-1930. Since this time, numerous natural and semi-synthetic antibacterial agents have been discovered and many of these introduced as chemotherapeutic agents to clinical use. However, over-use of these therapeutic agents within last 50 years has induced emergence of bacterial mutant resistance against these agents, thus, minimizing their therapeutic utilities as effective weapons in fighting infection.
Two parallel approaches are taken to overcome bacterial resistance. The first involves the development of agents to combat the bacterial resistance mechanism in order to revive the antibacterial potency of the parent molecule. These include, for example, inhibitors of β-lactamases and efflux pump inhibitors. The second approach focuses on novel antimicrobial agents with different targets and mechanism of action than those originally used (Mohsen Daneshtalab. Novel Synthetic Antimicrobials. Top Heterocycle Chem. Springer-Verlag Berlin Heidelberg 2006. 2:156-206). Unfortunately, slow progress has been made and additional new bacterial mutant resistance is on the rise.
The prevalence of bacterial resistance to conventional antibacterial agents has prompted multi-disciplinary scientists to search for antimicrobial targets with new antimicrobial agents. Certain bacterial targets, such as enzymes which participate in macromolecule synthesis, and are well characterized and hold promise for the discovery of novel antibacterial agents. For example, one target for discovery of a new class of anti-infectives is protein synthesis. Although there are similarities between the protein synthesizing machinery of prokaryote (microorganism) and eukaryote (mammalian) cells, there are sufficient differences that may be exploited for the development of new and selective antimicrobial agents. Bacterial aminoacyl-tRNA synthetases (aaRS) have been considered as promising antimicrobial targets because of their unique roles in protein biosynthesis (Vaughan M. D., et al. Investigation of Bioisosteric effects on the integration of substrates/inhibitors with the methionyl-tRNA synthetase from Escherichia coli. Medicinal Chemistry, 2005, 1:227-237; and Renau T. E., et al. Annual Reports in Medicinal Chemistry 1998, 33:121). Accordingly, it would be desirable to develop novel compounds which provide potential antimicrobial activity.
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